JCI online early table of contents: Dec. 6, 2010

EDITOR'S PICK: Alpha-2 integrin: a protein predictor of tumor
spread?

Mary Zutter and colleagues, at Vanderbilt University Medical
Center, Nashville, have generated data that lead them to suggest
that decreased expression of the protein alpha-2 integrin is
predictive of tumor dissemination to distant sites and decreased
survival in individuals with either breast or prostate cancer.

The researchers first studied the role of the protein
alpha-2-beta-1 integrin (which is composed of the alpha-2 integrin
protein and the beta-1 integrin protein) in cancer initiation and
progression using a clinically relevant, spontaneous mouse model of
breast cancer progression and metastasis (spread). Their data
indicated that alpha-2-beta-1 integrin suppressed metastasis. To
investigate whether the data had any immediate clinical
applicability, a systematic analysis of microarray databases of
human breast and prostate cancer was performed. The results of this
analysis showed that decreased expression of the gene responsible
for generating alpha-2 integrin was predictive of metastasis and
decreased survival, leading to the suggestion that alpha-2 integrin
expression could be a useful biomarker of metastatic potential and
patient survival.

TITLE: The alpha-2-beta-1 integrin is a metastasis suppressor in
mouse models and human cancer

The mammalian embryo relies on physical connections to its
mother to survive. After implantation into the wall of the uterus
and before the placenta is established, a structure known as the
decidua forms and is key to supporting embryonic development.
Defective formation of an effective decidua is thought to be a
cause of female infertility. A team of researchers, led by Toru
Miyazaki, at the University of Tokyo, Japan, has now determined
that the protein DEDD is required for the formation of a functional
decidua in mice. The authors therefore suggest that it would be
interesting to investigate whether DEDD dysfunction is the cause of
infertility in some women.

TITLE: Death effector domaincontaining protein (DEDD) is
required for uterine decidualization during early pregnancy in
mice

AUTHOR CONTACT:

Toru Miyazaki

Center for Disease Biology and Integrative Medicine, The University
of Tokyo, Tokyo, Japan.

Patients in hospitals and healthcare facilities can develop
infections as a result of contamination of indwelling medical
devices such as catheters with bacteria that are normal inhabitants
of the skin of the patient or health care personnel. The bacterium
Staphylococcus epidermidis is a major cause of such
infections. This is in part because of its ability to form biofilms
— surface-attached agglomerations of microorganisms that are
extremely difficult to eradicate — on indwelling devices.
Michael Otto and colleagues, at the National Institutes of Health,
Bethesda, have now identified the bacterial products that enable
Staphylococcus epidermidis biofilms to detach from the
surface to which they are adhered and cause infection in a mouse
model of catheterization. Importantly, molecules known as
antibodies that target these bacterial products inhibited bacterial
spread in the mouse model, leading the authors to suggest that
interfering with biofilm detachment mechanisms might provide a new
approach to preventing biofilm-associated infections.

Psoriasis is a common skin disorder that arises when immune
cells become overactive and generate unneeded inflammatory
responses in the skin. Dysregulated growth of new blood vessels
from pre-existing vessels (a process known as angiogenesis) is one
hallmark of psoriasis, which is also characterized by thick silvery
scales on affected areas of skin and itchy, dry, red patches. A
team of researchers, led by Michael Schön, at Georg August
University, Germany, has now found that reducing angiogenesis in
xenotransplantation models of psoriasis and in mice with a disease
that resembles psoriasis alleviates disease. They therefore suggest
that their non-viral gene therapy approach to reducing angiogenesis
might provide a new approach to treating psoriasis and, perhaps,
other inflammatory skin disorders characterized by dysregulated
angiogenesis.

VIROLOGY: How hepatitis C virus uses the cells it infects to
its own advantage

The current therapy to treat individuals infected with hepatitis
C virus (HCV) works in only about half of those treated. Therefore,
many individuals remain chronically infected with HCV, something
that often leads to liver failure and liver cancer. Research using
human liver cell lines, performed by Po-Yuan Ke and Steve Chen, at
Academia Sinica, Taiwan, has identified new ways in which HCV
coopts normal cellular processes in the cells that it infects to
enhance its reproduction and to evade certain aspects of the
antiviral immune response. These data not only provide new insight
into the ways in which interactions between HCV and the cells it
infects can benefit the virus, but also provide potential new
avenues of research for the development of novel therapeutic
approaches to clearing HCV infection.

PULMONARY: Pinpointing a role for the molecule TGF-beta in
lung scarring

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disorder
for which there are currently no treatments. It is a progressive
disease that results in lung scarring and changes in lung
architecture, which together lead to loss of lung function and
death. Although the cause(s) of IPF is unclear, dysregulated
signaling triggered by the molecule TGF-beta is known to have a
role in disease development. Parviz Minoo, Zea Borok, and
colleagues, at the University of Southern California, Los Angeles,
have now been able to more specifically pinpoint the role of
dysregulated TGF-beta signaling in disease development using a
mouse model of lung fibrosis (scarring).

The researchers generated mice lacking T-beta-RII — the
molecule to which TGF-beta binds to trigger a signaling cascade
— on cells lining the lung (epithelial cells). Importantly,
these mice showed increased survival and resistance to fibrosis in
the chemical-induced model of fibrosis studied. The authors
therefore suggest that T-beta-RII could provide a new target for
the development of therapeutics to treat IPF.

Individuals with mutations in their DES gene have dysfunctional
muscle fibers in their skeletal and heart muscle (conditions termed
myopathy and cardiomyopathy, respectively). This leads to
progressive skeletal muscle weakness and heart failure. A team of
researchers, led by Jocelyn Laporte, at the Institut de
Génétique et de Biologie Moléculaire et
Cellulaire, France, has now determined that the mechanisms
underlying disease in individuals with a previously unrelated form
of inherited myopathy (X-linked centronuclear myopathy [XLCNM]) are
similar to those in individuals with DES gene mutations.
Specifically, they found that the protein generated by the gene
mutated in individuals with XLCNM (MTM1) binds desmin (the product
of the DES gene) and ensures normal desmin expression and
localization in both both mouse and human skeletal muscles. These
and other data in the paper lead the authors to suggest that XLCNM
and desmin-related myopathy, two conditions thought previously to
be unrelated, have common disease-related features.

OPHTHALMOLOGY: Support for light-sensing cells eroded by the
mTOR signaling pathway

The retina is the light-sensitive tissue that lines the inner
surface of the eye. It consists of light-sensitive nerve cells
known as photoreceptors and cells that support and nourish the
photoreceptors, which are known as retinal pigment epithelial (RPE)
cells. RPE cell dysfunction leads to retinal degeneration and loss
of visual acuity. A team of researchers, led by Douglas Vollrath,
at Stanford University School of Medicine, Stanford, has now
determined in mice that stresses that disrupt the function of the
energy generating compartments within RPE cells (mitochondria)
trigger RPE cell dedifferentiation and that this leads to decreased
responsiveness of photoreceptor cells to light and their eventual
degeneration. Further analysis revealed that RPE cell
dedifferentiation involved the signaling protein mTOR and that the
mTOR inhibitor rapamycin protected photoreceptor function in
response to RPE stresses. The authors therefore suggest that mTOR
pathway inhibitors might provide a new approach to treating
individuals with retinal degenerative diseases involving RPE
stress.

Key to designing effective vaccines and immune-based
therapeutics for the treatment of autoimmune diseases such as
rheumatoid arthritis is characterizing in detail the immune cells
(T cells) that naturally respond to the microbe or cause the
autoimmune disease. One facet of this characterization is to define
very specifically the protein complex expressed by T cells (the T
cell receptor [TCR]) that enables them to "see" their target and
respond to microbes or cause autoimmunity. A team of researchers,
led by Paul Thomas, at St Jude Children's Research Hospital,
Memphis, has now developed a new method to examine the TCR
expressed by an individual T cell, an approach that they hope will
prove of tremendous use for researchers studying mouse models of
human disease.

TITLE: Paired analysis of TCR-alpha and TCR-beta chains at the
single-cell level in mice

(Journal of Clinical Investigation) This release contains summaries, links to PDFs, and contact information for the following newsworthy papers to be published online, Dec. 6, 2010, in the JCI: "Alpha-2 integrin: a protein predictor of tumor spread?;" "A DEDD cert to support embryo...